The Kuakini Medical Center (Kuakini) Hawaii Lifespan Study II will focus a multidisciplinary team of genetic, epidemiological, and geriatric scientists on the use of innovative approaches for secondary data analysis. We will use existing human data and specimens from the 45-year Kuakini Honolulu Heart Program/Honolulu Asia Aging Study (longitudinal studies of aging and chronic diseases), in Japanese-American men. Our work will focus on identifying the mechanism(s) of action of FOXO3A on healthy aging and longevity. We will attempt to identify novel genetic mechanisms by which people survive to older ages in good health. While terms such as successful, healthy or effective aging describe a paradigm of aging with minimal chronic disease, the genetic mechanisms of such aging are poorly understood. In recent work we have: 1) operationalized phenotypes of healthy aging that use performance-based measures of function 2) identified environmental predictors of healthy aging and longevity in a longitudinal study, (3) replicated a previous association of the CETP gene on longevity and extended the finding to include a role in healthy aging 4) and discovered a novel gene (FOXO3A) variation that is strongly associated with healthy aging and longevity. For the current study, a renewal proposal of our original parent R01-the Kuakini Hawaii Lifespan Study-we propose the following aims: 1) High density sequencing of the FOXO3A gene; 2) Repeat the original case-control study with 184 additional Kuakini HHP cases (n=397 longevity cases; 402 average-lived controls) in order to identify the strongest association with longevity; 3) Conduct a longitudinal study for incident diseases, functional loss and mortality with 3,569 Kuakini HHP subjects; 4) Conduct tests of association between genotypes and gene expression/protein function using cell lines from 287 Kuakini HHP subjects. Discovery of biologic pathways that affect vulnerability to age-related diseases and disability could have a dramatic impact on our ability to achieve healthy old age by identifying biological targets for new therapies. Our study directly supports NIA's mission to improve the health and well-being of older Americans.